cMET kinase is a receptor tyrosine kinase. HGF (hepatocyte growth factor, also known as scatter factor), the ligand for cMET, is secreted by cells of mesodermal origin whereas cMET is predominantly expressed on cells of epithelial/endothelial origin resulting in paracrine epithelial-mesenchymal cell signaling (Stoker, M. et al., Nature 327: 239-242 (1987)). Binding of HGF to the extracellular region of cMET activates the intracellular cMET tyrosine kinase activity. cMET is believed to be involved in protein phosphorylation events that regulate cell proliferation, apoptosis, motility, and dissociation of cell-cell interactions, morphogenesis, angiogenesis, and epithelial-mesenchymal transition. Misregulation of cMET can lead to unregulated cell proliferation and survival. cMET is thought to be a key regulator of invasive growth, cancer tumorgenesis, and progression to metastasis (Trusolino, T. and Comoglio, P. Nature Reviews Cancer: 2: 289-300 (2002)). cMET gene amplification, alteration, mutation, and protein over expression or activation of cMET through autocrine or paracrine mechanisms have been detected in a wide variety of carcinomas. For example, in human gastric cancer tissue, cMET has been found to be over expressed and amplified (Smolen, G. A., et al. PNAS 103: 2316-2321, (2006)). In human glioblastomas and carcinomas of lung, thyroid and breast, cMET has been found to be activated as a result of increased HGF levels and autocrine signaling (Birchmeier, C. et al. Rev. Mol. Cell Biol. 4: 915-925, (2003)). In human lung cancer tissue, cMET signaling has been found to be upregulated as a mechanism of drug resistance (Engelman, J. A., et al. Science 316: 1049-1043, (2007)). Activating mutations in cMET, although not as common, have been reported in sporadic and hereditary papillary renal carcinomas, head and neck squamous carcinomas as well as gastric and lung cancers. Furthermore, increased expression, the most common cMET alteration found in a wide variety of human tumors (including but not limited to renal, ovarian, hepatocellular, non-small cell lung, bone, liver metastasis of colon, oral squamous cell, esophageal, gastric, pancreatic, and prostatic cancers) correlates with poor prognosis (Benvenuti, S. and Comoglio, P. M., J. Cell. Physiol. 213: 316-325, (2007)).
There is a continued need to find new therapeutic agents to treat human diseases. Inhibition of cMET is an especially attractive target for the discovery of new therapeutics due to their important role in cancer and other diseases.